Process for drying organic pharmaceuticals



United States Patent PROCESS FOR DRYING ORGANIC PHARMACEUTICALS SidneyBeinfest, Berkeley Heights, Joseph Halpern, New Providence, SidneyGister, Bound Brook, and Phillip Adams and Michael Zelkind, BerkeleyHeights, N. J., assrgnors to Berkeley Chemical Corporation, BerkeleyHeights, N. J., a corporation of New Jersey Application November 20,1957, Serial No. 697,529

6 Claims. (Cl. 34-15) This invention relates to new and usefulimprovements in the obtaining of pharmaceuticals of high bulk density.More particularly it relates to a process of the nature indicatedwherein these pharmaceuticals, after initial processing, are treated asa high concentration of solids in a heterogeneous system with a volatileliquid and at a controlled temperature above the melting point of thepharmaceuticals to ultimately provide the improved products.

Many normally solid organic pharmaceuticals in order a to obtain therequisite purity after preparation are con-: ventionally crystallizedfrom volatile liquids, separated from most of the mother liquid bymechanical means, such as filtration or centrifugation, and then dried.

Their drying is done by standard'means, e. g. using rotary kiln,atmospheric shelf, and vacuum shelf dryers. All these methods result inproducts of rather low bulk density, e. g., for 2-methyl-2-n-propylpropane 1,3 dioldicarbamate, a well known tranquilizer, 0.30 to 0.37

gms./cc. This in turn results in low fiowability andconsequent clumpingin containers and hoppers. In addition as many of the crystals areelectrostatic,.dusting is a problem. These difficulties are particularlyundesirable in pharmaceuticals because of difficulty in'handling andpotential hazards from exposure of pharmacologically active dusts.

These physical characteristics further lead to problems.

in tabletting of the powders because of poor compressibility.Excessively large tablets are required for. stand-- Because of thesefactors wet granulation has been necessarywith' ard: dosages andconcomitant large packages.

consequent regrinding to improve fiowability. These expedients arecostly and tablet size is still larger than ob-' tained by the processof this invention.

This invention provides an improved method of overcoming all thesebeforementioned difficulties. The method comprises crystallizing thepharmaceutical from a volatile liquid, separating and removing amajorproportion of. .the liquid from the pharmaceutical-liquid system, toleave a high concentration of solid pharmaceutical product in aheterogeneous system with theresidual volatile liquid, stripping oil theremaining volatile liquid from the pharmaceutical, conveniently at asubatmospheric pressure, and at a temperature above the melting point ofthe pharmaceutical at the pressure utilized, but below its decompositiontemperature, under which conditions the pharmaceutical is liquid, thencooling the pharmaceutical to solidify it and finally comminuting it toobtain the high bulk density product. Further details follow.

It is surprising to learn that in this manner the bulk density can beimproved as much as 100%, e. g., for 2- methyl-Z-n-propyl-propane, 1,3diol dicarbamate from 0.35 to 0.7 gms./cc. after grinding. Thefiowability is increased and the need for wet granulation avoided. Thedried material can be tabletted directly or granulations can be preparedby dry slugging. All these advantages are obtained with a reduction indrying time requirements. The tablets produced have a volume de- 2crease of or more for the same dosage as compared... to tablets preparedfrom conventionally dried material.

The organic pharmaceuticals towhich this inventionis. applicable,arethose thatare normally solid (at conven-I tional atmosphericconditions), I have a decomposition. temperature at least 10 C. abovetheir melting points,. and arecapable of being purified bycrystallization from a volatile liquid. I l v C This invention isthusapplicable to pharmaceuticals" of a wide variety of chemicalstructures, e. g., esters,'j amides, ethers, diols and polyols, acids,phenols, keiton'es pyrimidines, etc. This invention is particularlysuitable to the class of materials selected from the group consisting of.alkanediols and .alkanediol dicarbamates. Examplesof specificcompoundstowhich this invention areapplicable include. butane, 1,3 dioldicarbamate, 2-meth yl-2-nepropyl-propa'ne' 1,3 diol dicarbamate, beta;glu q cosepentacetate, carbromal, barbital, acetyl carbromal, thymol,lauric acid, diethyl' stilboestrol, and mephenesina The volatile-liquidsfrom-which the organic pharmaceue ticals are crystallized orrecrystallized are water or typi cal-organicisolvents and mixtures ofthe two. The or naphtha, acetone, acetic acid, etc.

The actual crystallization procedure 1 is, nopart of 1 invention andneed notgbe elaboratedupon here. 7 4 The major proportionof the volatileliquid is then removed from the solid pharmaceutical-volatile liquid systern by mechanical separation such as centrifuging or filtration. f H

The removal of the major proportion of, the volatile liquid leaves ahigh concentration of solid pharmaceuticah in a heterogeneous systemwith the residual volatile liq-f uid. The term filter cake? is alsoutilized to connote this type system which normally has a liquid contentof about, 10 to 70 wt. percent, r H The remaining volatileliquid is'then stripped'ofi from the pharmaceutical at a temperature above themelting point of the pharmaceutical at the'pressure utilized, but" belowits decomposition temperature. The pressures can range-from sub tosuperatmospheric depending upon the solvent and temperature required.The pharmaceutical is thus liquid under these conditions. It is tobe,under -j{ :stood, of course, that the highly concentrated hetero-g;

geneous system can be heated to the desired controlled" temperatureprior to the application of the -pressure which is then utilized in thestripping operation. -The; temperatures given below refer to theterminal tempera tures since in heating up the system it will of coursehave to go through the lower temperatures first Finally the Ipressureutilized iseasily'chosen so as to permit the ob-x taining of thedesired temperature during-the stripping operation which willpermitmelting but not decomposi-;= tion. The exact temperature figuresvary from each compound, e. g. butane 1,3 diol dicarbamate, thetemperature utilized is in the range of about 152l70 C. and for2-methyl-2-n-propyl-propane 1,3 diol dicarbamate, it is in the range ofabout 107150 C. The

thrhigh-densityproduce is' obtained: Itis to' be-underdiiigiahfllTheremaining-volatile liquid is stiipped on froth the filter" cak'e iiithe kettle; the" pharmaceutical is" withdrawn through the" valve andsolidified as shown by flaking or 'casling.

This invention will be bttc r uhde'rstood by rer ience to the followingexamples of the treatmeiit of the ofgarlic pliarrhac e'utialacc'ordirig'" tothe process or this invention. Example Ir-Tlldtjfll'lltqf Z-nietliykZn-pfopyl prbpizhe p Li dlOldiCdlfbdMdtQ. 'K'filter cakeof' -Z rnethyFZ-mproPyI-propane- 1,3 diol (teammate crystalligfed fromxylol was placed-in a still anti heated to" 120 6., -l"- ab'ove itet'ruemeltingpoint, at which point it was: completely liquidL= The pressurewas flie'ii'redued 'to apoint at which the xylol distilled at convenientrate; maintainingthe temperature: at 120 1 30 C. by heating. As thes'olvent w'as' removed, the: was' reduced in: order to maintain therateofdis'tillation untilthe pressure' reached 15-'-20'.mmz and thedistillation ceased; The temperature 1 was maintained. The productwasremoved and cast-in trays. After solidifying by cooling} the pr'oductwas broken out and g r ohnd t'o the desired particle s'izein a hammermill;

The final product had a bulk density of 0.7' gmsrlccs after or about a"100% i'rnprovenientlover a control dried in atmospheric shelf drier. Thefinal product hl'ari all of the advantages listed before and none of thedisadvah't'ages of the cori'trol in further tabletting operauonsl- 1Example 2 venous other pns'raisemrens; were treated in a Sim ilar.mariner. as iii Ekaniple l. The details are presented be'low.

Mel ting Treat? Final 7, Pharmaceutical. Point, ment' Pres Solvent r C.1 Temp, .sure', C. mm.

, E v 50Hv81. percent Betaglucosepentace- 131-132 .150 20 5 z i percentF339: IPOH. Car-brornal 116-119 128' '20 xylol':

12 15 .xylol.

65' 15 99- vol. percent ,IPOH-. Laurie acid 44 100 15 ,507}; {)POH, 50%

2 1 Diethyl stilbesteroln 169-171: 185 80 benzene. Mephenesln 69- 110 20xylol.

In each casethe final product obtained by trleatrfidt above its meltingpoint had increased flowability and tabletting ease., The final bulkdensity can be varied according to particle size desired,

4 The advantagesofthisinvention have been listed and others will beapparent to the skilled in the art. Fine organic pharmaceuticals ofincreased bulk density, which are more easily amenable to subsequentprocessing, are economically obtained. Sincethe' solvents are distilled,

. they can be completely recovered by operating the condenser at asufiicieritlylow temperature. The'process has resulted in verysubstantial manufacturing savings.

It can also=be used where it is desired to screen or filter the meltedliquid' to remove foreign matter prior to chilling. V

If desired; and preferably, final'traces of volatile liquid can beremoved from the stripped molten pharmaceutical prior. to solidificationby blowing with an inertgas such as air, nitrogen or CO under vacuum.Steam is particularly effective.

The process is advantageously applicable to materials having physioloical: properties, e. g.- 4-,7 dichloroquinoline; whichas Ytar'e notusedas pharmaceuticals.

It is -u'nderstoodthat tl1i's inventionis notlimited to the specifi'eexampleswhiclihave been offered merely as illustrations andth'atmodifications may bemade without departing from the spirit" of theinvention.

What is claimed is? l;- A process for drying an organic pharmaceutical,

said organic pharmaceutical being normally solid and having adecor'riyio'sitidntenipera'tiire at least 10 C. above its melt'ingpointarid capable of being purified by crystalliia tion from a volatileliquid, which comprisesthe steps of cr'ystallizin'g thepharmaceuticalfrom the volatile liquid, separatin and removing a'- major proportionofthe volatile liquid-from the pharmaceutical-volatile liquid syste'mtoleave'a' highconcentration of solid pharmaeeutieal in' a heterogeneoussystemwiththe residual volatile liquid; stripping off remaining volatileliquid from the pharmaceutical ata temperature above the melting" pointof the pharmaceutical but below its decomposition temperature, atwhichtemperature the pharmaceuti'cal is liquid; cooling the strippedpharmaceutical to solidify it and then corii'minutihg it.

2. ,Theprocess ofclaim 1' in which the stripping step is" conducted at asuhatmosplierie pressure.

3. The process of claim 1 in which the volatile liquid isiafiorganicliquid.-

4. e process of claim 1 whieh the volatile liquid is water.-

5 The process ofclaim 1 in' which the pharmaceutical is dietliyl' s'tilboestr'ol.

6. The process of claim 1 in which the pharmaceutical is' niephenesin.

References Cited in the file of this patent UNITED STATES PATENTS560,561 Zappert May 19, 1896 1,557,880 Richter Oct. 20, 1925 2,001,658Williams May 14, 1935 2,295,745 Merriam Sept. 15, 1942 2,439,384 FetzerApr. 13, 1948

1. A PROCESS FOR DRYING AN ORGANIC PHARMACEUTICAL, SAID ORGANICPHARMACEUTICAL BEING NORMALLY SOLID AND HAVING A DECOMPOSITIONTEMPERATURE AT LEAST 10*C. ABOVE ITS MELYING POINT AND CAPABLE OF BEINGPURFIED BY CRYSTALLIZATION FROM A VOLATILE LIQID, WHICH COMPRISES THESTEPS OF CRYSTALLING THE PHARMACEUTICAL FROM THE VOLATILE LIQUID;SEPARATING AND REMOVING A MAJOR PROPORTION OF THE VOLATILE LIQUID FROMTHE PHARMACEUTICAL-VOLATILE LIQUID SYSTEM TO LEAVE A HIGH CONCENTRATIONOF SOLIDSPHARMEACUTICAL IN A HETERGENEOUS SYSTEM WITH THE RESIDUALVOLATILE LIQUID; STRIPPING OFF REMAINING VOLATILE LIQUID FROM THEPHARAMEACEUTICAL AT A TEMPERATURE ABOVE THE MELTING POINT OF THEPHARMACEUTICAL BUT BELOW ITS DECOMPOSITION TEMPERATURE, AT WHICHTEMPERATURE THE PHARMACEUTICAL IS LIQUID; AT WHICH TEMPERATURE THEPHARMACEUSOLIDIFY IT AND THEN COMMINUTING IT.